Synthesis and Evaluation of 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides as Novel GSK‐3β Inhibitors and Anti‐Ischemic Agents
Synthesis and Evaluation of 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides as Novel GSK‐3β Inhibitors and Anti‐Ischemic Agents
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DOI：
10.1111/cbdd.12546
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发表时间：
2015-10
影响因子：
3
通讯作者：
Q. Ye;Qiu Li;Yubo Zhou;Lei Xu;Weili Mao;Yuan-xue Gao;Chenhui Li;Yuan Xu;Ya-zhou Xu;H. Liao;Luyong Zhang;Jian-rong Gao;Jia Li;Tao Pang
中科院分区：
文献类型：
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作者：
Q. Ye;Qiu Li;Yubo Zhou;Lei Xu;Weili Mao;Yuan-xue Gao;Chenhui Li;Yuan Xu;Ya-zhou Xu;H. Liao;Luyong Zhang;Jian-rong Gao;Jia Li;Tao Pang
设计、合成了一系列3-（呋喃并[2，3-B]吡啶-3-基）-4-（1H-吲哚-3-基）-马来酰亚胺类化合物，并对其GSK-3β抑制活性进行了生物活性评价。大多数化合物对GSK-3β蛋白表现出良好的抑制活性。其中，化合物5 n、5 o和5 p显著降低原代神经元中GSK-3β底物tau在Ser 396处的磷酸化，表明细胞GSK-3β活性的抑制。在体外神经元损伤模型中，化合物5 n、5 o和5 p防止了与脑缺血性中风密切相关的谷氨酸、氧-葡萄糖剥夺和营养血清剥夺的神经元死亡。在体内脑缺血动物模型中，化合物50使梗塞面积减少10%并改善神经功能缺损。这些结果可能为开发具有潜在神经保护活性的新型GSK-3β抑制剂提供新的见解，以对抗脑缺血性卒中。
A series of novel 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides were designed, synthesized, and biologically evaluated for their GSK‐3β inhibitory activities. Most compounds showed favorable inhibitory activities against GSK‐3β protein. Among them, compounds 5n, 5o, and 5p significantly reduced GSK‐3β substrate tau phosphorylation at Ser396 in primary neurons, indicating inhibition of cellular GSK‐3β activity. In the in vitro neuronal injury models, compounds 5n, 5o, and 5p prevented neuronal death against glutamate, oxygen–glucose deprivation, and nutrient serum deprivation which are closely associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 5o reduced infarct size by 10% and improved the neurological deficit. The results may provide new insights into the development of novel GSK‐3β inhibitors with potential neuroprotective activity against brain ischemic stroke.